As a candidate for the NIH Pathway to Independence Award, my immediate goal is to gain experience in diabetes and cardiovascular research with Dr. Louis Ragolia, Director of the Vascular Biology Institute at Winthrop University Hospital (WUH), as my mentor. WUH is a major teaching hospital in the New York area and will provide an ideal environment for the ultimate development of my independent research career. The proposed research will integrate my experience in bone and cartilage biology with the research objectives of my mentor. The aims of the proposal will test the hypothesis that elevated HPA hormone activity in diabetes promotes the chondrogenic differentiation associated with atherosclerotic lesions after initial endothelial dysfunction and lipid deposition, leading to increased cartilage metaplasia and ultimately increased arterial adluminal calcification. In Aim 1, methods traditionally used to study dynamic mineralization in bone will be applied to the quantification of cartilage metaplasia and mineralization in a novel model of type 2 diabetes, the lipocalin-type prostaglandin D2 synthase knockout (L-PGDS KO) mouse. Aims 2A and 2B will focus on the identification and isolation of the cellular source of cartilage metaplasia in the vasculature and examine the cellular response to HPA hormones with and without an intact extracellular matrix. Lastly in Aim 3, the atherosclerosis-prone, ApoE-deficient mouse will be crossed with the corticotropin releasing hormone (CRH) deficient mouse. These mice will be treated with streptozotocin (STZ) to create a model of diabetes-induced chronic stress in the setting of a suppressed HPA axis. Cartilage metaplasia and mineralization associated with endochondral differentiation in atherosclerotic lesions of STZ-treated ApoE (-/-), CRH (-/-) and ApoE (-/-)/CRH (-/-) mice will be quantified using outcome measures optimized during the mentored phase. Upon the successful completion of the proposal aims we expect to have identified a new therapeutic target in the treatment and prevention of calcified atherosclerosis. These studies will serve as a solid foundation on which I will build an independent research program;one that bridges the study of mineralizing tissue with the study of cardiovascular disease progression. (End of Abstract)